Hantavirus cardiopulmonary syndrome (HCPS) is a major cause of morbidity and mortality (38% case fatality rate) in Chile where 60-81 cases per year have been reported in the last 3 calendar years. There is no treatment of proven efficacy, but we have established an effective hantavirus clinical trials network in Chile and have a placebo-controlled trial of intravenous methylprednisolone (MP) in progress that will reach 75% of its target accrual by July 2005 and can be completed in year 1 of this proposal. This will be the first completed efficacy trial for HCPS. Based on our findings that neutralizing antibody titers are lower at hospital admission in persons with severe/fatal HCPS as compared to mild HCPS in Sin Nombre virus infection in the US and Andes virus infection in Chile as well as the ability of neutralizing antibody to protect from lethal disease in the Andes virus/hamster model, we have begun collection of plasma with high neutralizing antibody (hantavirus immune plasma or HIP) by plasmapheresis from survivors of Andes virus infection. In this project, we propose to a) complete the controlled trial of MP in HCPS in year 1; b) continue collection of plasma by plasmapheresis of survivors of Andes virus infection in years 1-5; c) perform three clinical trials with HIP. The first trial with HIP will be a phase I, dose-escalation safety and pharmacokinetics trial in a) normal adults and b) persons with HCPS to be performed in year 2. The second trial will be an open safety and efficacy trial of HIP in persons at high risk of developing HCPS (sex partners of index patients with HCPS who have a 20% risk of developing HCPS) that will be performed in years 3-5. The third trial will be a controlled trial of HIP in persons with suspected HCPS in the cardiopulmonary phase that will also be performed in years 3-5. These studies have the potential to provide effective, safe preventive therapy for persons at risk of HCPS and safe, effective treatment for persons with HCPS in the cardiopulmonary phase. They can also discourage the use of any therapy found to be unsafe and/or ineffective.